Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

International audienceMotile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum

Les marqueurs mémoriels de la guerre et de l’armée

La mémoire est devenue un élément majeur de nos sociétés contemporaines. Si elle peut s’appuyer sur des témoins vivants, elle s’ancre sur le long terme grâce à une matérialité inscrite dans le paysage : les marqueurs mémoriels. En Alsace et en Lorraine, l’armée et les guerres constituent des éléments clefs de la mémoire collective, dans un espace aux frontières mouvantes au gré des siècles et des conflits armés. De cette histoire, des marqueurs permettent d’en avoir une lecture et fournissent des outils de compréhension pour l’observateur attentif : ce sont bien entendu des monuments, des casernes et autres infrastructures militaires, comme aussi des églises, noms de rue, un habitat particulier. La lecture de ces marqueurs permet de saisir, comme des reliques, une histoire et une mémoire d’un espace déterminé.Memory has become a major element of our contemporary societies. If it can be based on living witnesses, it is anchored in the long term thanks to a materiality inscribed in the landscape: the memorial markers. In Alsace and Lorraine, the army and the wars are key elements of the collective memory, in an area with borders that have shifted over the centuries and armed conflicts. The markers of this history allow us to read it and provide tools for the attentive observer to understand it: these are of course monuments, barracks and other military infrastructures, as well as churches, street names and a particular habitat. The reading of these markers makes it possible to grasp, like relics, a history and a memory of a given space

International Health Practices: A Multidisciplinary Approach to Therapeutic Mediations With an Artistic Medium Based on the Model of Play

International audienceThis article, corresponding to a part of the restitution of a financed international research project between France, Brazil, Canada, Italy and Belgium, aims to offer a modelisation and qualitative evaluation of mediation care settings based on an original methodological tool that involves identifying the typical games at the foundations of creativity, following a multidisciplinary perspective. Therapeutic mediations are settings or devices organized around a "pliable medium," often artistic, like painting, modeling, writing and theater, which are very widespread in institutional practices, both in France and abroad. The scientific objectives of this research consist in a multi-disciplinary exploration (anthropology, criminology, neuroscience, clinical psychology) of the process of creative symbolization understood as a process of transformation involving play. According to this orientation, play can be defined as a psychic process whereby a subjective experience can be explored with pleasure, and consequently symbolized and appropriated. Our fundamental and original hypothesis is that play is at the source of the creative process, conceived as a work of metabolization by the psyche of playful experiences during the different stages of life. The review of the understanding of play in psychoanalysis, anthropology, criminology and neuroscience emphasizes the richness of this model and the importance of reflecting on the typical games in the field of psychic care. A clinical example of treatment in a pictorial therapeutic mediation setting of a child with psychotic disorders makes it possible to identify a number of typical games as well as the modalities of interpretation of the therapists through play. These multidisciplinary studies lead to the presentation of a general table of typical games, and these first results highlight the richness of identifying typical games in clinical settings. Ultimately, the multidisciplinary approach shows the interest of the model of play in the evaluation of therapeutic mediation settings, with a convergence of the different disciplines emphasizing the pertinence of this model. The scientific impact of this research overlaps with its societal impact, through the development of innovative tools for evaluating therapeutic mediations, in order to take account of the evolution of the different forms of social expression of psychic suffering

Intellectuels en diaspora et théories nomades

Ce numéro vise à rendre compte de la complexité et de la variabilité des relations qu'entretiennent les cultures, les hommes et les savoirs d'ici et d'ailleurs, en particulier entre l'Inde et l'Occident. C'est l'occasion de souligner l'importance que revêtent aujourd'hui les circulations des expériences vécues et des connaissances, lesquelles permettent de reconfigurer la division internationale du travail scientifique et de redistribuer les cartes du débat sur les questions du postcolonialis..

TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella

International audienceCilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella

TTC12 loss-of-function mutations cause primary ciliary dyskinesia and unveil distinct dynein assemblymechanisms in motile cilia versus flagella

International audienceCilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs/IDAs). Defects in ODAs/IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. To date PCD mutations in assembly factors cause a combined ODA/IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the sole absence of IDAs in respiratory cilia. We analysed both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach, as well as TTC12 depletion in the ciliated model, Paramecium tetraureli. Our results revealed an IDA defect restricted to a subset of single-headed IDAs different in flagella and cilia, while TTC12 depletion in Paramecium tetraurelia recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a new gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella